Basal cell carcinomas (BCCs) are the most common cancer in the US with an annual incidence of 750,000. The highly stromal-dependent growth of BCCs makes them ideal models for the analysis of tumor-stromal interactions. Recently the central role of the Sonic hedgehog (Shh) signaling pathway in the epithelium of these tumors has been elucidated. Their preliminary evidence supports the hypothesis that the surrounding tumor stroma regulates BCC growth by controlling the transcriptional induction of Shh target genes in the epithelium. Greater knowledge is needed to understand mechanistically how stromal cells accomplish this crucial function. The aim of this grant is identify the stromal cells and genes that regulate epithelial Shh target gene induction to maintain BCC growth and malignant potential. They proposes to: 1) Determine why keratinocytes fail to induce the Gli genes in the absence of a stromal environment; 2) Identify the stromal cells which allow epithelial Shh target gene expression in organotypic skin cultures; and 3) Identify candidate stromal signaling genes using high density cDNA arrays. At the end of the proposed funding period they will have a greater mechanistic understanding how epithelial Shh target genes are regulated by signals from the surrounding stroma. Their studies should give insight into how the growth of other epithelial tumors are regulated by their stroma and may lead to the development of new anti-tumor agents.